Previously considered a disease of the peripheral nervous system (PNS), there is mounting evidence to support concomitant involvement of the CNS in diabetic neuropathy. Involvement of the spinal cord has been reported in post-mortem studies, which demonstrated axonal loss, gliosis, and demyeli-nation within the spinal cord (2-6). However, many of these studies did not examine patients with diabetic neuropathy specifically; therefore, it is not possible to conclude whether these changes were due to neuropathy or diabetes.
The reason why some patients develop painful neuropathic symptoms is far from clear. These can occur with little objective evidence of peripheral nerve dysfunction and can be extremely distressing and difficult to treat. Electrical spinal cord stimulation has been used to alleviate pain, which is unresponsive to conventional treatment (7). However, it has been observed that this technique is ineffective in subjects with severe loss of vibration and joint position sense, which has led to the suggestion that the spinal cord may have a role in pain modulation. In a preliminary study, using a non-invasive MR imaging technique, Eaton et al. explored possible involvement of the spinal cord in DPN (8). Onmeasuring cross-sectional area of the spinal cord at three different levels (lower cervical, upper, and lower thoracic regions), they reported significantly lower cord area in the cervical and upper thoracic regions in subjects with established-DPN compared to healthy non-diabetic controls indicating extensive disease in these areas. Diabetic subjects with no-DPN appeared to have intermediate cord area measurements between non-diabetic controls and established-DPN. These results would suggest that the abnormalities previously reported in post-mortem studies do reflect a neuropathic process affecting the spinal cord. One theory postulates that damage to the peripheral nerve causes secondary spinal cord 'shrinkage' due to degeneration or atrophy. Another theory is that the primary insult may be to the CNS, with the well-documented peripheral changes occurring as secondary phenomena. It is also conceivable that both peripheral and CNS involvement occur concomitantly resulting in the findings documented.
In order to examine these theories further, and as the relevance of these findings to the pathogenesis of DPN is dependent on whether spinal cord shrinkage occurs early, a larger, adequately powered study was conducted. In this study 98 subjects with type 1 diabetes were subdivided into three subgroups (no-DPN, subclinical-DPN, and established-DPN), and spinal cord area measurements were performed at the level C2/C3 (9). Diabetic subgroup measurements were compared with 24 non-diabetic healthy controls and 8 subjects with hereditary sensory motor neuropathy (HSMN). The latter group was chosen to serve as disease controls because it is well recognised to affect only the PNS and vascular factors have not been implicated in its pathogenesis. In this larger study, the results of the pilot study were confirmed and, more importantly, also clearly demonstrated that spinal cord atrophy is an early process being present not only in established-DPN but also even in subjects with relatively modest impairments of nerve function (subclinical-DPN) (Fig. 1). It was also demonstrated that a significant trend of lower cord cross-sectional area with more severe neuropathy occurred across diabetic groups indicating a continuing loss of cord area as the disease progresses. Significant correlations were found between cord area and neurophysiological parameters of neuropathy severity. Cord area was not significantly different between age-matched and sex-matched non-diabetic controls and diabetic subjects without DPN. Approximately 26% and 9% of patients with clinical-DPN and subclinical-DPN, respectively, were found to have spinal cord atrophy (Fig. 2) (9). In contrast, unlike DPN, subjects with HSMN (neuropathy control group) had normal cord areas suggesting that the pathological process here is confined to the peripheral nerve.
The findings of this clinical study show that the neuropathic process in diabetes is not confined to the peripheral nerve and does involve the spinal cord. Worryingly, this occurs early in the neuropathic process. Even at the early DPN stage, extensive and perhaps even irreversible damage may have occurred. Indeed, with these results in mind, it is not surprising that the variety of therapeutic options so far attempted in DPN have not been successful (10). The absence of spinal cord involvement in HSMN argues against a 'dying back' mechanism, i.e. peripheral nerve damage causing secondary spinal cord 'shrinkage' in a progressive 'dying back' fashion, in DPN.
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